Inflammatory Bowel Disease (IBD), which includes ulcerative colitis and Crohn's disease, is one of the five most prevalent gastrointestinal diseases in the USA. The overall cost exceeds $1.7 billion, affecting as many as 1.4 million individuals in the USA and 2.2 million individuals in Europe. IBD accounts for more than 700,000 physician visits, 100,000 hospitalizations, and disables 119,000 patients annually in the United States alone. Although the etiology of IBD remains unclear, chronic gut inflammation results from excessive immune responses to enteric microbes. Current therapies including anti-inflammatory drugs (such as anti-TNF or anti- integrin antibodies) and other immunosuppressive regimens have limited efficacy, significant toxicities, and can be extremely expensive. Despite significant progress in disease management, curative treatment options are not yet available. High mobility group box 1 (HMGB1), a cytokine mediator of inflammation, has recently been implicated in the pathogenesis of IBD. Neutralization of HMGB1 activity improves clinical scores in the animal models of colitis. Accordingly, here we propose to develop synthetic beads coated with oligonucleotides to specifically capture and remove HMGB1 from the gut. These oligo-beads will be administered orally, or via enema, to sequester HMGB1 from the intestinal surface in IBD patients. Should the proposed approach prove successful, oligo- beads will be developed into a product to treat IBD, and the technology expanded to other ailments targeting specific molecules.